Synergistic interactions of cytarabine-adavosertib in leukemic cell lines proliferation and metabolomic endpoints.

Drug synergy allows reduced dosing, side effects and tolerance. Optimization of drug synergy chemotherapy is fundamental in acute lymphocytic leukemia and other cancers. This study aimed to analyze the pharmacodynamic synergy between the anti-metabolite cytarabine and WEE1 inhibitor adavosertib on acute leukemia cell lines CCRF-CEM and Jurkat. In both cell lines analysis of concentration-inhibition curves of adavosertib-cytarabine combinations and synergy matrixes supported mutually synergistic drug interactions. Overall mean ( ± SD) synergy scores were higher in Jurkat than CCRF-CEM: Jurkat, ZIP 22.51 ± 1.1, Bliss 22.49 ± 1.1, HSA 23.44 ± 1.0, Loewe 14.16 ± 1.2; and, CCRF-CEM, ZIP 9.17 ± 1.9, Bliss 8.13 ± 2.1, HSA 11.48 ± 1.9 and Loewe 4.99 ± 1.8. Jurkat also surpassed CCRF-CEM in high-degree synergistic adavosertib-cytarabine interactions with mean across-models synergy values of ∼89.1% ± 2.9 for 63 nM cytarabine-97 nM adavosertib (91.4% inhibition synergy barometer). Combination sensitivity scores scatter plots confirmed combination's synergy efficacy. This combined approach permitted identification and prioritization of 63 nM cytarabine-97 nM adavosertib for multiple endpoints analysis. This combination did not affect PBMC viability, while exhibiting Jurkat selective synergy. Immunoblots also revealed Jurkat selective synergistically increased γH2AX phosphorylation, while CDC2 phosphorylation effects were attributed to adavosertib's WEE1 inhibition. In conclusion, the high synergistic efficacy combination of cytarabine (63 nM) and adavosertib (97 nM) was associated with remarkable alterations in metabolites related to the Krebs cycle in Jurkat. The metabolic pathways and processes are related to gluconeogenesis, amino acids, nucleotides, glutathione, electron transport and Warburg effect. All above relate to cell survival, apoptosis, and cancer progression. Our findings could pave the way for novel biomarkers in treatment, diagnosis, and prognosis of leukemia and other cancers.

Ultrasound-Guided A1 Pulley Release: A Systematic Review.

The purpose of this review was to summarize the current literature pertaining to ultrasound-guided percutaneous A1 pulley release procedures. We searched PubMed, Cochrane Library, Embase, and Web of Science for clinical studies examining ultrasound-guided percutaneous A1 pulley release. A total of 17 studies involving 749 procedures were included in this review. The overall success rate was 97%. There were 23 minor complications (4 cases of hematomas, 15 cases of persistent pain, and 4 cases of transient numbness) and no major complications reported. Ultrasound-guided A1 pulley release is an effective and safe procedure for the treatment of trigger fingers and thumb.

Lateral epicondylitis: comparing ultrasound-guided tenotomy with or without amniotic membrane allograft injection.

Aim: To evaluate the clinical response to augmenting ultrasound-guided tenotomy (USGT) with an amniotic membrane (AM) allograft injection. Design: Retrospective study. Materials & methods: Subjects underwent either a USGT (N = 16) or a combined USGT plus AM injection (N = 14). Results: Both groups demonstrated a significant reduction in pain from baseline starting after 2 weeks in the USGT plus AM group (p = 0.036) and after 8 weeks in the USGT group (p = 0.021). The reduction in pain was sustained for the entire duration of the study (52 weeks). There was no significant difference in pain levels at 26- or 52-week follow-up or patient satisfaction between the two groups. Conclusion: USGT with or without AM allograft injections results in a significant reduction in pain with high patient satisfaction.

The goal of this study was to determine if a single injection of an amniotic membrane (AM) tissue improves clinical outcomes for patients with chronic tennis elbow treated with ultrasound-guided tenotomy. Ultrasound-guided tenotomy involves using a cutting device to remove degenerative tissue with ultrasound-guidance to help tendon's healing process. An AM injection is thought to reduce inflammation in the surrounding tissue, provide growth factors that help with the tendon's healing process, and minimize painful scar formation. 30 patients were included in this study (16 ultrasound-guided tenotomy [USGT] and 14 USGT plus AM injection). Both groups showed improvement in pain levels compared with their baseline at the short-term follow-up, and this reduction in pain was sustained for 52 weeks. There were no long-term differences between the two groups at the 52 week follow-up in pain levels or satisfaction. Our findings suggest that USGT, with or without AM injection, is an effective method of treatment for chronic tennis elbow.

Pseudoseptic reaction to an intra-articular platelet-rich plasma injection into the knee: a case report.

A variety of intra-articular injections are used for the management of osteoarthritis. A rare complication of intra-articular injections is acute pseudoseptic arthritis, which mimics true septic arthritis. To the authors knowledge, pseudosepsis has not been reported as a complication after platelet-rich plasma (PRP) injections. We present a case report of pseudoseptic arthritis resulting in acute postinjection pain and a joint effusion after an intra-articular PRP injection into the knee. Clinically, pseudosepsis can occur after PRP treatment with significantly elevated white blood cell counts in the synovial fluid, and should be a consideration in cases of post-PRP injection flares.

Heterotopic Mineralization of the Medial Collateral Ligament: Our Experience Treating Two Cases of Calcific Versus Ossific Lesions With Ultrasonic Vacuum Debridement.

Chronic injury to the medial collateral ligament (MCL) is common following an acute knee injury. This case report presents two patients that failed to respond to conservative treatment with clinical evidence of an MCL injury and radiographic finding of a benign-appearing soft tissue lesion in the MCL. Calcified or ossified lesions have been described with chronic MCL injuries. Ossification and calcification of the MCL have been observed as potential causes of chronic MCL pain. Here, we detail the distinction between these two distinct intra-ligamentous heterotopic deposits and describe a novel treatment approach using ultrasonic percutaneous debridement, a technique that is typically reserved for tendinopathies. In both cases, pain improved, and they were able to return to their prior level of function.

Plantar fasciitis: a comparison of ultrasound-guided fasciotomy with or without amniotic membrane allograft injection.

Aim: The purpose of this study was to evaluate the clinical response to augmenting an ultrasound-guided percutaneous plantar fasciotomy (UGPF) with an amniotic membrane (AM) allograft injection. Design: Retrospective, single-center, matched, case-controlled study. Methods: Patients underwent either an UGPF (n = 15) or a combined UGPF and AM injection (n = 16). Results: The UGPF plus AM group demonstrated a significant reduction in pain (p = 0.02) from baseline at the short-term follow-up, but there was no significant difference in pain or patient satisfaction between groups at the 52-week follow-up. Conclusion: Both groups demonstrated a significant reduction in pain and high level of patient satisfaction, but the combination of UGPF with an AM injection may provide a greater reduction in pain earlier in the post-operative period.

Calcific Tendinopathy of the Shoulder: A Retrospective Comparison of Traditional Barbotage Versus Percutaneous Ultrasonic Barbotage.

OBJECTIVE: The purpose of this study was to compare a traditional barbotage technique with percutaneous ultrasonic barbotage (PUB) for the treatment of rotator cuff (RC) calcific tendinopathy. DESIGN: Three-year retrospective review. SETTING: Participants aged 18 to 75 presenting at 2 highly specialized outpatient orthopedic referral centers with symptomatic RC calcific tendinopathy. PATIENTS: There were 75 patients included (23 patients in the traditional barbotage group; 52 patients in the PUB group) with an average age of 55.3(6.5) and 55.9(9.8), respectively. There was no significant difference in demographics between groups. INTERVENTIONS: Traditional barbotage or PUB. MAIN OUTCOME MEASURES: Primary outcome measure was pain rated on the Numeric Pain Rating Scale (NPRS) with secondary outcomes investigating patient satisfaction. RESULTS: The barbotage and PUB group demonstrated a significant improvement in pain (barbotage 2.4, P = 0.01; PUB = 2.6, P < 0.001) with no statistically significant difference between the 2 treatment modalities (95% CI: -1.8 to 2.2; P = 0.83, P = 0.83). Median follow-up for NPRS recordings was 17-weeks in the barbotage group and 8-weeks in the PUB group ( P = 0.004). Both groups demonstrated similar patient-reported satisfaction, without major complications. CONCLUSION: The traditional barbotage and PUB procedures improved pain with a high patient satisfaction rate. LEVEL OF EVIDENCE: Level III.

Chronic Medial Collateral Ligament Sprain Treated With Percutaneous Ultrasonic Debridement: A Case Report.

ABSTRACT: The medial collateral ligament (MCL) is the most commonly injured ligament of the knee. Most grade I and II injuries respond to conservative management, but symptoms persist in some patients. In these cases, treatment options are limited. Percutaneous ultrasonic debridement is increasingly being used for tendinopathy and fasciopathy refractory to conservative management, but this has not been reported as a treatment for ligament injury. Here, we present a case of a chronic grade II MCL sprain successfully treated with percutaneous ultrasonic debridement.

Osteitis Pubis Treated With Platelet-Rich Plasma: A Case Report.

ABSTRACT: Osteitis pubis is a common source of groin pain in athletes participating in sports requiring kicking, twisting, and pivoting movements. Athletes will present with progressive pain or discomfort in the pubic area or groin. There is usually point tenderness over the pubic symphysis and pain localizing to the adductor or rectus abdominis tendons. Conservative management often includes activity modification, oral medications, progressive rehabilitation, therapeutic ultrasound, steroid injections, and prolotherapy. Osteitis pubis can be refractory to conservative management and can keep an athlete sidelined for as long as 2 years. Platelet-rich plasma (PRP) injections have been used for pubic symphysis pain, but reports have focused on pathology affecting the rectus abdominis or hip adductor muscle tendons. In this article, we present a case of isolated osteitis pubis, without overlapping rectus abdominis or adductor tendon involvement, successfully treated with an ultrasound-guided PRP injection of the fibrocartilage.

Percutaneous ultrasound-guided resection of a painful osteophyte using novel Tenex-Bone device in a residual limb: A case report.

Residual limb pain is common after amputation. Painful osteophytes are one of many causes of residual limb pain, and cases that fail conservative management may require open surgical resection. Here we present a novel percutaneous ultrasound-guided approach to remove a painful osteophyte in a transfemoral amputee. This procedure successfully treated this patient's residual limb pain while minimizing the risks associated with open surgical resection.

Expression of nuclear progesterone receptor, progesterone receptor membrane components 1 and 2 and prostaglandin-endoperoxide synthase 2 in the endometrium and oviduct of spontaneously ovulating cats.

Although ovulations not followed by pregnancy occur regularly in cats, differences in endometrial function between cats in the luteal and non-luteal phase have not been studied so far. Progesterone exerts its effects through a nuclear progesterone receptor (PGR) and via cell-membrane bound receptors referred to as progesterone receptor membrane component (PGRMC) 1 and 2. Progesterone receptor expression is regulated by gonadal steroid hormones and therefore may change throughout the oestrous cycle. Protein expression of PGR, PGRMC-1 and 2 and prostaglandin-endoperoxide synthase 2 (PTGS2) was analysed in the endometrium and oviduct of non-pregnant female cats in the follicular (n = 8) and luteal phase (n = 9). We hypothesized that the presence of corpora lutea (CL) is associated with downregulation of progesterone receptors and PTGS2. Cells of the luminal endometrial epithelium, endometrial stroma and oviductal epithelium were assessed by immunohistochemistry. The PGR protein expression was more pronounced in the endometrial epithelium than stroma (p < 0.001) and less pronounced in cats with a CL than without CL (p < 0.001) but did not differ between groups in the oviduct. The PTGS2 was localized only in the endometrial and oviductal epithelium and its expression was reduced in cats with CL (p = 0.001). In the endometrial epithelium, PGRMC-1 expression was reduced in cats with CL (p < 0.05). Expression of PGRMC-2 was highest in the endometrial epithelium and lowest in the endometrial stroma (p = 0.01) but did not differ between cats with and without CL. In conclusion, progesterone receptor and PTGS2 downregulation in the female cat closely resembles findings in other spontaneously ovulating domestic animal species.

Suggested Curricular Guidelines for Musculoskeletal and Sports Medicine in Physical Medicine and Rehabilitation Residency Training.

ABSTRACT: A sports medicine physician manages musculoskeletal (MSK) injuries and sport-related medical and MSK conditions of patients of all ages and abilities. Physical medicine and rehabilitation physicians (physiatrists) must be adequately trained to provide this care for all patients including, but not limited to, athletes participating in organized sports, the weekend warrior as well as athletes with disabilities. Accreditation Council of Graduate Medical Education core requirements and basic guidelines help physiatry residency training programs develop and implement residency curriculums. The goal of this article is to provide suggested curricular guidelines to optimize physiatrist training in MSK and sports medicine.

A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19.

BACKGROUNDAlthough convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.METHODSWe conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.RESULTSOf 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83-2.68, P = 0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22-0.91, P = 0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.CONCLUSIONIn adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A possible explanation is that survivors remained hospitalized at their baseline clinical status.TRIAL REGISTRATIONClinicalTrials.gov, NCT04359810.FUNDINGAmazon Foundation, Skoll Foundation.

Subluxing fractured plantar fat pad: a case series and description of novel sonographic findings.

Plantar fat pad syndrome has received little attention in the literature. A variety of structural changes of the plantar fat pad have been described in the literature, including atrophy, contusion, and fractured fat pad. This case series presents 4 patients (5 heels) with subluxation of a fractured plantar fat pad on dynamic ultrasound. Patients with subluxing fractured fat pad typically present with heel pain and a "snapping" or "popping" sensation when weight-bearing. Other causes of heel pain were excluded, and all patients in this series had an MRI that initially did not report any findings in the fat pad. Retrospective review of the MRI showed evidence of diffuse low T1 and T2 infiltration. To the authors' knowledge, subluxation of the plantar fat pad and the respective correlation to MRI findings have not been described in the literature. Here we describe the sonographic findings of this novel condition.

Simplifying the Execution of HepatoPac MetID Experiments: Metabolite Profile and Intrinsic Clearance Comparisons.

The HepatoPac micropatterned coculture (MPCC) hepatocyte system has been shown to be an effective tool to investigate the qualitative human and preclinical species' metabolite profiles of new drug candidates. However, additional improvements to the overall study conditions and execution, layout, and human-donor count could be made. To that end, we have evaluated several ways to increase the amount of data one can generate per MPCC plate and how to more efficiently execute a MPCC study for the purpose of metabolite generation. Herein, we compare a set of compounds using single- and 10-donor pooled human MPCC hepatocytes. Intrinsic clearance and mean metabolic activities assessed by diverse enzyme markers were comparable between the single- and 10-donor pool. We have confirmed that the generated metabolite profiles were indistinguishable between the single- and 10-donor pool and also that rat MPCC can be performed at 400 µl media volume, which greatly simplifies study execution. Additional tips for successful study execution are also described. SIGNIFICANCE STATEMENT: When using the HepatoPac micropatterned coculture (MPCC) system, sometimes simple experimental condition variables or problematic plate designs can hamper productive study execution. We evaluated conditions to increase the amount of data one can generate per MPCC plate and, perhaps more importantly, execute that study more efficiently with less likelihood of error. We describe some of our key learnings, provide an examination of enzyme activity levels and clearance values, and provide some recommendations to simplify the execution of a HepatoPac experiment.

Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes.

BACKGROUND: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. METHODS: Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. RESULTS: Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of samples and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. CONCLUSIONS: We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.

Influence of graft size, histocompatibility,and cryopreservation on reproductive outcome following ovary transplantation in mice.

PURPOSE: Transplantation of ovarian tissue is a valuable method to rescue mouse strains with fertility problems and to revitalize archived strains. The purpose of this study was to investigate the effect of (i) different sizes of transplanted ovary pieces on reproductive outcome, (ii) use of immunodeficient recipients to overcome the limitation of histocompatibility, and (iii) to compare different protocols for cryopreservation of ovarian tissue. METHODS: Halves, quarters, and eights of mouse ovaries were transplanted. Half ovaries from B6 donors were transferred into immunodeficient mice. Halves of ovaries were frozen according to four different protocols, thawed and transferred. RESULTS: Pregnancy rate after transplantation of ovarian tissue was high (90-100%) independent of the transplant size. Although, the average litter size was significantly lower for recipients of quarters and eights (4.4 and 4.6 vs. 6.5), the total number of offspring produced per donor ovary was higher compared with recipients of halves. Pregnancy rate of immunodeficient recipients was 40% (mean 4.7 offspring per litter). All four cryopreservation protocols used were able to preserve functionality of the ovarian tissue. CONCLUSIONS: Transplantation of ovarian tissue smaller than halves resulted in reduced litter sizes. The distribution of ovarian tissue of one donor female to 4 or 8 recipients will therefore yield in a higher total number of offspring in a certain time period. The use of immunodeficient recipients is an option for non-histocompatible donors. Cryopreservation of ovarian tissue is generally feasible but the function of frozen-thawed ovary halves after transplantation differs depending on the freezing protocol used.